Wound healing is a series of reactions that repair the defects of epithelial tissues in the skin and the like, being one of the most organized immune or inflammatory reactions. A wound healing reaction proceeds in three stages: (1) inflammation stage (2) granulation stage, and (3) remodeling stage. In the inflammation stage, an inflammatory reaction is induced locally upon tissue damage, and neutrophils and macrophages migrate to the wounded site. Macrophages secrete various inflammatory cytokines and chemokines to enhance the inflammatory reaction. In the following granulation stage, angiogenesis is induced by proliferation of vascular endothelial cells, and at the same time fibroblasts infiltrating the wounded site proliferate and produce extracellular matrix such as collagen to form granulation tissue for tissue regeneration. Furthermore, fibroblasts in the granulation tissue differentiate into myofibroblasts, which are rich in actin and highly contractile. The wound contraction, which is mainly mediated by the myofibroblasts, is a useful tool for efficiently reducing wound areas. In the remodeling stage, epithelial cell formation is induced on the granulation tissue, where the original normal structure is remodeled. Impaired wound healing reaction, accompanied with systemic or local pathological conditions, leads to treatment-resistant wounds such as bedsores, postoperative infections at wounded sites, diabetic ulcers, and burns. On the other hand, execessive wound healing reaction causes various fibrotic disorders, for example, keloidosis and scar in the skin, and airway remodeling in asthma in the lungs. In severer cases, the exaggerated wound healing may cause scleroderma, pulmonary fibrosis, liver cirrhosis and the like. For this reason, this series of wound healing reactions must be strictly controlled. Although cytokines such as TGFβ and IL-6, and growth factors such as PDGF and FGF, are reported to play important roles in the progression of wound healing reactions, it remains unclear how these reactions are regulated.
PDLIM2 (PDZ and LIM domain protein-2), also known as SLIM (STAT-interacting LIM protein), is a nuclear ubiquitin ligase, which was isolated by the present inventors. PDLIM2 has both PDZ and LIM domains and belongs to LIM protein family. PDLIM2 binds to STAT4, a transcription factor essential to Th1 cell differentiation in T cells, in the nucleus, and terminates STAT4-mediated signal transduction by ubiquitinating and degrading STAT4 protein (Non-patent Document 1, Patent Document 1). Later analysis revealed that PDLIM2 is a nuclear ubiquitin ligase for NF-κB, terminating inflammatory responses by ubiquitinating, degrading and inactivating NF-κB in dendritic cells (Non-patent Document 2, Patent Document 2). PDLIM2 deficiency in dendritic cells results in defective NF-κB degradation and the production of two- to three-fold more proinflammatory cytokines. However, in vivo functions of PDLIM2 remain unclear so far.    [Patent Document 1] Specification for US-B-application No. 2006/246543    [Patent Document 2] JP-A-2007-254465    [Non-patent Document 1] Tanaka et al., Immunity, 22, 729-736, 2005    [Non-patent Document 2] Tanaka et al., Nat. Immunol. 8, 584, 2007